Serotonin(1A) receptor agonism in the expression of behavioral dopaminergic supersensitivity in subchronic haloperidol treated rats.
The idea that serotonin (5-hydroxytryptamine; 5-HT) is contributed in schizophrenia has long been advocated and alterations in 5-HT neurotransmission has been hypothesized to modulate both the therapeutic and extrapyramidal symptoms (EPS) liability of conventional neuroleptics. The 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a preferential 5-HT(1A) ligand, has been reported to attenuate EPS functions of haloperidol in animals. In view of a possible role of 5-HT(1A) receptors in the management of EPS functions of a neuroleptic drug, the present study was designed to investigate behavioral responses of 8-OH-DPAT at a challenge dose of 0.5mg/Kg in rats with subchronic haloperidol administration at a dose of 5mg/Kg twice daily for 5 days. The intensity of 5-HT syndrome provoked by 8-OH-DPAT was taken as a measure of postsynaptic responses. In the present study administration of haloperidol at a dose of 5mg/Kg twice daily for 5 days decreased locomotion significantly (p<0.01) in familiar (home cage) environment. Subchronic administration of haloperidol at the same dose elicited significant (p<0.01) cataleptic responses in rats when compared with saline treated rats. Results revealed that 8-OH-DPAT-induced hyperlocomotion (p<0.05) and forepaw treading (p<0.1) were significantly smaller in rats pre-treated with haloperidol for 5 days than repeatedly saline injected rats. Conversely, the other components of the syndrome i.e. flat body posture (p<0.001), hind limb abduction (p<0.001) and straub tail (p<0.01) were significantly greater in repeated haloperidol treated rats when compared with repeated saline injected rats. These findings help to demonstrate a causal link between the upregulation of DA-D(2) receptors and the decrease in the effectiveness of presynaptic 5-HT(1A) receptors following subchronic haloperidol administration and this may further help to yield an antipsychotic agent with an improved profile of efficacy to EPS, thereby widening its therapeutic window.
Batool
Farhat
F
Neurochemistry and Biochemical Neuropharmacology Research Laboratory, Department of Biochemistry, University of Karachi, Karachi-75270, Pakistan. batool@uok.edu.pk
Haleem
Darakhshan J
DJ
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D006220:Haloperidol; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D017661:Receptors, Presynaptic / Q000819:agonists* / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D020230:Serotonin Syndrome / Q000139:chemically induced / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D017448:Receptors, Dopamine D2; D017661:Receptors, Presynaptic; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006220:Haloperidol